This is the second revision of a renewal for year five to continue work on the design of antibody molecules that target the product of a mutated oncogene with the eventual aim of creating as useful treatment reagent. The targeted protein is p185, a product of neu that is known to be expressed at high frequency in several forms of breast cancer. Particular aggressive forms of breast adenocarcinoma involve the synergistic activity of p185 and the EGF receptor. Specific Aim 1 proposes to study small forms of the most efficacious anti-receptor antibody molecules able to convert the malignant phenotype of human breast cancer cells into a normal one. It is argued that small forms are needed to overcome critical limitations of intact immunoglobulins which include poor and incomplete penetrance of tumor mass and variable entry into some compartments of the body. The idea is to extend work on single chain form and CDR-derived forms of anti-p185 and anti-EGFR that are known to be active on cells in culture. The goal is molecules which can simultaneously down-regulate either p185 alone or in combination with the EGFR on human cancer cells in vitro and in vivo. Another idea is to link GM-CSF to these antibodies with the hope that enhanced cell-mediated immunity against the tumors will be induced. The second aim is to define the role of genes that may play a role in anti-receptor antibody mediated conversion of the malignant phenotype. Using differential display a member of a new family of growth related genes was identified. The conditions which allow expression of this cDNA will be defined as will the ability of the encoded protein to suppress the malignant phenotype. Other "normal phenotype" associated proteins and genes will be sought.